Summary Basis of Decision for Lynkuet

Clinical Pharmacology

Elinzanetant (the medicinal ingredient in Lynkuet) is a non-hormonal, selective, dual neurokinin 1 (NK-1) and 3 (NK-3) receptor antagonist that blocks receptor signaling on kisspeptin/neurokinin B/dynorphin (KNDy) neurons, which are hyperactivated due to estrogen decline in menopause. Neurokinin 1 and 3 antagonism with Lynkuet modulates neuronal activity involved in thermoregulation.

Elinzanetant has a high affinity for human NK-1 receptors (mean inhibitory constant [K_i] value of 0.37 nM) and NK-3 receptors (mean K_i value of 3.0 nM).

The pharmacokinetics of elinzanetant was thoroughly studied in healthy subjects, and the results are expected to be applicable to patients with vasomotor symptoms (VMS). Following oral administration, elinzanetant is rapidly absorbed, with a median time to maximum plasma concentration (T_max) of one hour and an absolute bioavailability of 52%. The observed increase in elinzanetant exposure, as measured by the maximum plasma concentration (C_max) and the area under the plasma concentration-time curve (AUC) was greater than dose-proportional (20% to 50%) over the dose range of 40 to 160 mg once daily. Steady-state plasma concentrations of elinzanetant are expected to be reached by Day 5 to 7. The terminal half-life of elinzanetant is estimated to be 45 hours, with modest accumulation (two-fold or lower). The majority of the administered dose is excreted by the fecal route, with less than 1% of the dose excreted in urine. Following a high-fat and high-calorie meal, the AUC and C_max of elinzanetant were significantly reduced. However, the trough concentration (C_trough) was not reduced. Lynkuet can be taken with or without food.

No dosage adjustment is recommended for patients with mild hepatic impairment. A 2.3-fold increase in total elinzanetant exposure was observed in patients with moderate hepatic impairment. Lynkuet is not recommended for use in individuals with moderate hepatic impairment. Additionally, Lynkuet has not been studied in individuals with severe hepatic impairment and is not recommended in this population.

Based on population pharmacokinetic analysis, the total exposure of elinzanetant is expected to be similar between patients with mild and moderate renal impairment and patients with normal renal function. No dose modification is required for individuals with mild or moderate renal impairment. However, renal impairment may affect protein binding; an increase in the unbound portion of elinzanetant was observed in patients with moderate or severe renal impairment. As the unbound portion of elinzanetant exposure increases with the severity of renal impairment, Lynkuet is not recommended for use in individuals with severe renal impairment. The pharmacokinetics of elinzanetant has not been studied in patients with end stage renal disease and is not recommended in this population. No clinically relevant differences on the pharmacokinetics of elinzanetant were observed with respect to effects of age, body mass index, or race.

Concomitant use of elinzanetant with cytochrome P450 (CYP) 3A4 inducers or inhibitors can change elinzanetant exposure to varying degrees. Patients receiving moderate to strong CYP3A inducers could experience a reduction in efficacy; however, no dosage adjustment is recommended. A strong CYP3A4 inhibitor can increase the exposure of elinzanetant up to 6.3-fold, and therefore the concomitant use of elinzanetant with strong CYP3A4 inhibitors is contraindicated. For patients taking moderate CYP3A4 inhibitors, the recommended daily dose of Lynkuet is reduced to 60 mg/day. Elinzanetant and weak CYP3A4 inhibitors can be administered concomitantly without any dose adjustment. Elinzanetant itself is a weak inhibitor of CYP3A4. Caution is required when co-administering Lynkuet with sensitive CYP3A4 substrates with a narrow therapeutic window.

The potential for drug interactions between elinzanetant and tamoxifen (which is metabolized to its active metabolites by CYP3A4) was examined. The exposure of tamoxifen and its metabolites were not significantly altered when taken concomitantly with elinzanetant. Therefore, no dose adaptation of tamoxifen is required. No dosage adjustments are necessary when Lynkuet is administered with proton pump inhibitors or substrates of breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1/1B3, and P-glycoprotein (P-gp) transporters.

Exposure of elinzanetant in the human brain was examined through clinical positron emission tomography (PET) studies. Simulations predicted that at C_trough, 90% of women with VMS are expected to have over 95% occupancy of the NK-1 receptor and over 80% occupancy of the NK-3 receptor. Thus, almost complete receptor occupancy can be expected throughout the dosing period. In postmenopausal women with VMS, no relevant or consistent changes in sex hormone concentrations were observed with elinzanetant in clinical trials. No clinically relevant prolongation of the corrected QT (QTc) interval was observed after single oral administration of elinzanetant at doses up to five times the maximum recommended dose. Although elinzanetant is not likely to have a clinically meaningful effect on driving ability, patients are advised to avoid driving or operating machinery if they experience adverse events such as fatigue, dizziness or somnolence during treatment with elinzanetant, which are considered common adverse events in clinical trials. The additive effects of elinzanetant on alcohol-induced psychomotor and cognitive symptoms are considered minimal, not clinically relevant, and do not require additional precautions beyond what normally should be taken by individuals following alcohol consumption.

For further details, please refer to the Product Monograph for Lynkuet, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Lynkuet was primarily established based on data from two pivotal Phase III studies, studies 1 (study 21651) and 2 (study 21652). The studies were identically designed, each consisting of a 12-week randomized, double-blind, placebo-controlled treatment period, followed by a 14-week active treatment extension without placebo control. Both studies enrolled postmenopausal women 40 to 65 years of age experiencing moderate to severe vasomotor symptoms (VMS) associated with clinically or hormonally confirmed menopause. Subsets of the study population included participants with a history of hysterectomy (38.8%), oophorectomy (20.6%), or prior hormone replacement therapy (HRT) use (31.4%). Participants eligible for the study had reported 50 or more moderate to severe episodes of VMS in the seven days prior to randomization.

The prevalence of early menopause (less than 45 years of age) and premature menopause (less than 40 years of age) was notably high across both studies. Early menopause was reported in 26.8% and 11.8% of participants in the Lynkuet arm in studies 1 and 2, respectively. Premature menopause was reported in 24.4% and 11.1% of participants in the placebo arm, respectively.

Thirty-five percent (35%) of participants were current or former smokers, with a balanced distribution across treatment arms in the pooled analysis. In study 1, smokers (current or former) were more common in the placebo arms (41.7% in the placebo arm and 24.7% in the Lynkuet arm), while in study 2, the reverse was observed (41.5% in the Lynkuet arm and 32.5% in the placebo arm).

Across both studies, 399 participants were treated with Lynkuet 120 mg once daily (number of participants [n] = 199 in study 1 and n = 200 in study 2), while 397 participants received a placebo (n = 197 in study 1 and n = 200 in study 2).

The primary efficacy endpoints in both studies were the mean change from baseline in the frequency of moderate to severe hot flashes at Weeks 4 and 12, assessed using the Hot Flash Daily Diary (HFDD). The two key secondary efficacy endpoints were the mean change from baseline in the severity of moderate to severe hot flashes at Weeks 4 and 12. Statistically significant improvements were observed in groups treated with Lynkuet (versus placebo) across all four VMS efficacy endpoints (the two primary and the two key secondary endpoints) in both studies at Weeks 4 and 12.

In study 1, the mean daily VMS frequency in the Lynkuet arm was reduced by 7.60 episodes at Week 4 and by 8.66 episodes at Week 12, compared to reductions of 4.31 and 5.44 episodes, respectively, in the placebo arm. In study 2, the corresponding reductions were 8.58 and 9.72 episodes in the Lynkuet arm, and 5.54 and 6.48 episodes in the placebo arm.

The treatment-effect estimate of Lynkuet versus placebo exceeded two episodes per day at both time points in both studies, indicating a clinically meaningful benefit. The between-group differences at Week 4 were 3.29 episodes in study 1 (p <0.0001) and 3.04 in study 2 (p<0.0001), remaining stable through Week 12 (3.22 and 3.24 episodes, respectively; p<0.0001 for both).

With respect to VMS severity, in study 1, Lynkuet reduced mean VMS severity scores by 0.73 and 0.92 points at Weeks 4 and 12, respectively, compared to 0.40 and 0.52 points with placebo, resulting in treatment differences of 0.33 (p<0.001) and 0.40 points (p<0.001). In study 2, reductions with Lynkuet were 0.75 and 0.91, versus 0.53 and 0.62 with placebo, corresponding to treatment differences of 0.22 (p = 0.0003) and 0.29 points (p<0.001), respectively.

Indication

The New Drug Submission for Lynkuet was filed by the sponsor with the following proposed indication, which Health Canada subsequently approved:

Lynkuet (elinzanetant) is indicated for the treatment of moderate to severe vasomotor symptoms (VMS) associated with menopause.

For more information, refer to the Product Monograph for Lynkuet, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The safety profile of Lynkuet was characterized based on data from the two pivotal Phase III studies (studies 1 and 2 [n = 393 and n = 400 respectively], described in the Clinical Efficacy section above) and a long-term placebo-controlled study (study 21810) conducted over 52 weeks in 313 postmenopausal women receiving Lynkuet 120 mg daily (n = 627).

The most commonly reported adverse drug reactions (in at least 2% of participants and reported more frequently than in participants receiving placebo) during the 12-week placebo-controlled periods of pivotal studies 1 and 2 included headache (8.5% versus 2.5%), fatigue (6.5% versus 1.8%), gastroesophageal reflux disease (3.0% versus 0.5%), dizziness (2.8% versus 1.0%), somnolence (2.5% versus 0.5%), and abdominal pain (2.0% versus 0.5%).

Similar adverse events were observed in the 52-week study with slightly higher incidences, including headaches (9.6% versus 7.0%), fatigue (7.3% versus 2.9%), somnolence (5.1% versus 1.3%), abdominal pain (4.5% versus 2.5%), diarrhea (3.8% versus 1.0%), dizziness (3.8% versus 1.6%), muscle spasms (3.2% versus 0.6%), and rash (3.2% versus 1.3%). No new safety signals were observed in the long-term study, consistent with what was seen in the pivotal trials.

Serious adverse events were rare (reported in 1.2% of participants treated with Lynkuet and 0.9% of participants who received placebo) and generally deemed unrelated to treatment. One seizure occurred during the open-label phase and was possibly related, but confounded by medical history. Four thromboembolic and cardiovascular events were reported: two cases of pulmonary embolism, one transient ischemic attack, and one myocardial infarction. Although causality has not been established, these events support the need for continued monitoring. Discontinuations due to adverse events were more frequent with Lynkuet than with placebo (7.8% versus 3.6%), most of which were attributed to fatigue and headache. Temporary treatment interruptions were also higher in participants who received Lynkuet than in those who received placebo (3.5% versus 2.5%).

Liver enzyme elevations (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase) were more common with Lynkuet but were typically mild, transient, and asymptomatic. Twelve cases warranted close liver observation and three met criteria for potential liver injury, but none fulfilled Hy’s Law. No clinically significant liver injury occurred. Given previous concerns within this drug class and limited long-term data, ongoing hepatic safety surveillance is recommended.

Endometrial safety was assessed by analyzing 609 endometrial biopsies collected during the Phase III program. No hyperplasia or malignancy was detected, including in patients with 12 months of exposure. However, the upper 95% confidence interval for hyperplasia slightly exceeded internationally accepted guidelines of a 2.0% threshold, indicating the need for further long-term evaluation. Postmenopausal bleeding was rare and similar between groups, although more events were classified as treatment-related in the Lynkuet arm, possibly reflecting functional unblinding due to fatigue or somnolence. No consistent signal for abnormal bleeding was identified.

Palpitations occurred approximately three times more frequently with Lynkuet than with placebo. These were generally mild and may relate to vasomotor symptomatology, complicating the causality assessment. Nonetheless, palpitations are included as a potential adverse reaction, and patients should be monitored accordingly.

Photosensitivity was uncommon, mild to moderate, and primarily observed with longer treatment duration. No significant safety differences emerged across subgroups by body mass index (BMI), race, or ethnicity, though central-nervous system (CNS)-related adverse events were more frequent in White participants compared to Black participants. Dose-ranging data indicate increased somnolence and dizziness at doses above 120 mg, supporting 120 mg as the optimal balance between efficacy and tolerability.

The generalizability of the safety data is limited by the selective trial population and underrepresentation of patients with significant comorbidities. Approximately 30% of screened individuals were randomized, and the longest period from which safety data could be collected was 12 months, in 300 participants. While the safety data meet regulatory requirements, further characterization of longer-term safety is needed and will be a focus of post-marketing risk management.

No clinical safety data are available in breast cancer patients, a population with high unmet need for non-estrogen therapies. The ongoing study 21656 aims to address this gap.

In summary, elinzanetant at the recommended dose of 120 mg (2 × 60 mg capsules) demonstrated an overall favourable safety profile in postmenopausal women with moderate to severe vasomotor symptoms. Most adverse events were mild, transient, and occurred early in treatment. Serious adverse events were rare. Hepatic and endometrial safety require continued monitoring. Key uncertainties remain around thromboembolic risk, hepatic effects, and use in special populations. The benefit-risk-uncertainty profile is favourable when used with appropriate risk mitigation and post-marketing surveillance.

For more information, refer to the Product Monograph for Lynkuet, approved by Health Canada and available through the Drug Product Database.

The efficacy and safety profiles of elinzanetant and its principal human metabolites were characterized in comprehensive non-clinical studies. All pivotal safety-related studies were compliant with Good Laboratory Practices (GLP).

In primary pharmacodynamics studies, elinzanetant was found to non-competitively bind to and antagonize the human neurokinin 1 (NK-1) and 3 (NK-3) receptors, with inhibitory constants (K_i) of 0.37 nM and 3.0 nM, respectively. Elinzanetant displayed a higher (approximately 8-fold) affinity for the NK-1 receptor than the NK-3 receptor. Affinities of the principal metabolites M30/34 (major), M27, and M18/21 to the NK-1 and NK-3 receptors were comparable to those observed with elinzanetant. Findings from in vivo pharmacodynamic studies indicated that orally administered elinzanetant acts centrally by inhibiting NK-1 and NK-3 receptor agonist-induced neurobehavioral responses. The efficacy of elinzanetant was not investigated in any animal models of human menopause.

In secondary pharmacodynamic studies, no clinically relevant secondary pharmacological targets were identified for elinzanetant and its key human metabolites. Safety pharmacology studies did not show any clinically relevant adverse effects on the central nervous system, cardiovascular system, or respiratory system. Pharmacokinetic profiles of elinzanetant in the rat and monkey, the species used in the toxicity program, were similar to the profile of elinzanetant observed in humans. After oral administration, elinzanetant absorption was rapid, the volume of distribution was large, and elimination was slow. Elinzanetant binding to plasma proteins, particularly human serum albumin, was high across all animal species tested, which is similar to observations in humans (99.7%). Elinzanetant crosses the blood-brain barrier, with peak levels of radioactivity in the brain approximately 6 to 10 times lower than in the blood. The pattern of elinzanetant metabolism was largely similar across species, with no unique human metabolites observed. Elinzanetant is mainly metabolized by cytochrome P450 (CYP) 3A4, with smaller additional contributions by CYP3A5 and uridine diphosphate glucuronosyltransferase (UGT) enzymes. Elinzanetant and its principal metabolites are irreversible inhibitors of CYP3A4. Elinzanetant and its metabolites were primarily excreted via the fecal route.

No mortality was observed in single-dose toxicity studies performed with orally administered elinzanetant in rats, marmosets, and monkeys. Acute elinzanetant-related effects restricted to signs of gastrointestinal toxicity were observed in monkeys. In repeat-dose toxicity studies, safety margins (the ratio of animal to human elinzanetant exposure, as measured by the area under the plasma concentration-time curve [AUC]) were moderate to high in rats and low in monkeys. The key target organs and systems identified were the female reproductive system (abnormal diestrus), central nervous system (tremor, spasms), skeletal muscle (involuntary contractions), and gastrointestinal system (emesis, loose/soft feces). Adaptive hepatocyte hypertrophy was observed in the pivotal 39-week monkey study.

Elinzanetant was not found to be genotoxic in a battery of tests, including the Ames test, the mouse lymphoma gene mutation assay, and a rat in vivo bone marrow micronucleus test. There were no elinzanetant-related neoplasms in the mouse 6-month carcinogenicity study. In the 2-year carcinogenicity study in rats, increases in uterine neoplasms and malignant lymphoma incidence rates were observed in female rats. However, based on the high margins of exposure (29 times the maximum recommended human dose) and an apparent rat-specific mechanism for uterine neoplasms, elinzanetant is not considered to have clinically relevant carcinogenic potential.

Elinzanetant did not impair fertility and was not teratogenic, but was embryotoxic in rats based on an observed increase in pre- and post-implantation loss. Elinzanetant and its metabolites crossed the placenta in rats and were excreted in the milk of lactating rats. Lynkuet is therefore contraindicated during pregnancy and is not recommended in breastfeeding individuals.

Elinzanetant did not induce withdrawal syndrome, serve as a clear discriminative stimulus, or induce reinforcing effects in monkeys. Elinzanetant was phototoxic in an in vitro phototoxicity study. The clinical effects of the prolonged retention of elinzanetant in the skin is not known, as elinzanetant binding to melanin was evident from high and prolonged exposure in pigmented skin and uvea.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Product Monograph for Lynkuet. Considering the intended use of Lynkuet, there are no pharmacological or toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Product Monograph for Lynkuet, approved by Health Canada and available through the Drug Product Database.

The quality (chemistry and manufacturing) information submitted for Lynkuet has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper pharmaceutical development and supporting studies were conducted and an adequate control strategy is in place for the commercial processes. Changes to the manufacturing process and formulation (if any) made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 30 months is acceptable when the drug product is stored at room temperature (15 ºC to 25 ºC). Lynkuet must not be frozen.

The proposed drug-related impurity limits are considered adequately qualified (e.g., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [ICH] limits and/or qualified from toxicological studies, as needed).

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy).

All sites involved in production are compliant with good manufacturing practices.

The biologic raw materials used during manufacturing originate from sources with no or minimal risk of transmissible spongiform encephalopathy (TSE) or other human pathogens.